Translating a miRNA Signal into Physical Immunomodulation via Programmed DNA Network Assembly on Mitochondria

Precision immunotherapy is critically hampered by the nonspecific toxicity of cGAS–STING pathway agonists. We overcome this fundamental barrier with a programmable DNA nanomaterial that operates as a logic-gated theranostic agent at the organelle level. Our nanodevice targets mitochondria and uses an integrated catalytic circuit to decipher the presence of oncogenic microRNA-21 (miR-21). Upon positive identification, it triggers the in situ architectural assembly of a physically disruptive DNA network on the mitochondrial surface. This targeted structural stress inflicts profound membrane damage, weaponizing the tumor cell’s own mitochondrial DNA as a precision-guided agonist to ignite a powerful, localized STING-mediated immune assault. This strategy provides a dual function, enabling amplified diagnostic imaging of its molecular trigger while orchestrating the profound suppression of both primary and metastatic tumors in vivo with undetectable systemic toxicity. This work establishes a new design principle for intelligent therapeutics and defines a new therapeutic paradigm, the direct conversion of a fleeting molecular signal into a stable, physical, and immunomodulatory structure, forging a new frontier for dynamic materials in precision medicine.